OVERALL PROGRAM SUMMARY/ABSTRACT Alzheimer?s disease (AD) is a devastating progressive neurodegenerative disorder affecting >6 million older people in the USA for which there is no viable treatment option. Accordingly, defining the earliest cellular and molecular mechanisms that drive the preclinical phase of dementia to develop novel disease modifying therapeutics is a public health priority worldwide. The thrust of our PPG entitled ?Neurobiology of Mild Cognitive Impairment in the Elderly? continues to be to elucidate the cellular and molecular basis or chain of events leading from no cognitive impairment (NCI) to mild cognitive impairment (MCI), the time-points considered the most likely therapeutic windows for treating dementia. Moreover, we continue to focus our efforts on NCI subjects with AD pathology suggestive of preclinical AD, in order to resolve the molecular and cellular neuropathogenic sequela underlying this preclincal stage of the disease. We will implement a series of interrelated connectome projects centered on the cholinergic basal forebrain (CBF)-default mode network (DMN) circuit, which is critical for memory and executive function and displays early pathology and biomaker activity prior to MCI (prodromal AD). CBF neuron dysfunction plays a pivotal role in the onset of clinical dementia and is the basis for the majority of FDA approved drugs for AD. This PPG competitive renewal application continues to bring together a number of basic and clinical scientists with multidisciplinary, complementary expertise in preclinical AD to investigate circuit-based neuronal system dysfunction at the earliest stages in the disease process. The PPG includes an Administrative & Clinical/Tissue Distribution Core, a Statistics & Data Management Core and three research projects titled: Tau Abnormalities and Mild Cognitive Impairment in the Elderly Scott Counts, Project Leader, PL, Michigan State University, Cholinergic Basal Forebrain Neurotrophic Abnormalities and Mild Cognitive Impairment in the Elderly (Elliott Mufson, PL, Barrow Neurologic Institute/Banner Alzheimer?s Institute), and Synaptic and Cholinergic Abnormalities in Mild Cognitive Impairment in the Elderly (Milos Ikonomovic, PL University of Pittsburgh). The Cores support each Project and all Projects interact intellectually, scientifically, and thematically. All Cores and Projects utilize the same Rush Religious Orders Study (RROS) cases and tissues for continuity, which confers the ability to correlate biologic measures with cognitive and neuropathological criterion. The lack of true animal models and a lack of efficacy of current drugs make our human clinical pathological studies particularly relevant for understanding mechanisms of preclinical AD.